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【结 构 式】 
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【分子编号】69465 【品名】(R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol 【CA登记号】 |
【 分 子 式 】C19H19FN4O3 【 分 子 量 】370.383 【元素组成】C 61.61% H 5.17% F 5.13% N 15.13% O 12.96% |
合成路线1
该中间体在本合成路线中的序号：(IV)Deprotection of the 6-benzyloxypyrrolotriazine (I) by transfer hydrogenation with ammonium formate and Pd/C in DMF provides alcohol (II) , which is condensed with (R)-propylene oxide (III) in the presence of triethylamine , and optionally LiCl , in ethanol at 70 °C to give the hydroxypropyl derivative brivanib (IV) . Subsequent coupling of alcohol (IV) with N-Cbz-L-alanine (V) by means of HATU in the presence of DIEA and DMAP in DMF or THF gives the N-protected alanine ester (VI), which is finally deprotected by treatment with ammonium formate and Pd/C in DMF . Alcohol intermediate (II) is alternatively obtained by addition of methylmagnesium bromide to the 6-(ethoxycarbonyl)pyrrolotriazine derivative (VII) in THF to afford the tertiary alcohol (VIII), which undergoes oxidative cleavage to the key 6-hydroxypyrrolotriazine (II) in the presence of H2O2 and BF3·Et2O in dichloromethane .
| 【1】 Bhide, R.S., Cai, Z.W., Zhang, Y.Z. et al. Discovery and preclinical studies of (R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem 2006, 49(7): 2143-6. |
| 【2】 Cai, Z.-W., Qian, L., Bhide, R., Barbosa, A. (Bristol-Myers Squibb Co.).Novel inhibitors of kinases. EP 1434290, JP 2005538989, US 2004072832, US 6869952, WO 2004009784. |
| 【3】 Cai, Z.W., Zhang, Y.Z., Borzilleri, R.M. et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem 2008, 51(6):1976-80. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 69463 | 6-(benzyloxy)-4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine | C23H19FN4O2 | 详情 | 详情 | |
| (II) | 69464 | 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol | C16H13FN4O2 | 详情 | 详情 | |
| (III) | 62110 | (R)-(+)-PROPYLENE OXIDE; 1,2-Epoxypropane; R(+)-Propylene oxide; R(+)-Methyloxirane; (R)-propylene oxide; [(R-(+)-1,2-EPOXYPROPANE]; (R)-(+)-1,2-Propylene oxide; (R)-(+)-1,2-Epoxypropane | 15448-47-2 | C3H6O | 详情 | 详情 |
| (IV) | 69465 | (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol | C19H19FN4O3 | 详情 | 详情 | |
| (V) | 10445 | N-Carbobenzyloxy-L-alanine;N-Benzyloxycarbonyl-L-alanine;Carbobenzyloxy-L-alanine;Z-L-Alanine;Z-Ala-OH;BenzyloxycarbonylLalanine;N-Cbz-L-alanine | 1142-20-7 | C11H13NO4 | 详情 | 详情 |
| (VI) | 69466 | (R)-(S)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl 2-(((benzyloxy)carbonyl)amino)propanoate | C30H30FN5O6 | 详情 | 详情 | |
| (VII) | 69467 | ethyl 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate | C19H17FN4O3 | 详情 | 详情 | |
| (VIII) | 69468 | 2-(4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)propan-2-ol | C19H19FN4O2 | 详情 | 详情 |